BackgroundKabuki syndrome (KS) is a multisystem genetic disorder caused predominantly by pathogenic variants in KMT2D or KDM6A, characterized by developmental delay, congenital anomalies, and immune dysregulation. Autoimmune cytopenias are an important hematologic manifestation in KS; however, their clinical and immunological correlations remain insufficiently defined. This study aimed to compare the clinical and immunological features of KS patients with and without autoimmune cytopenias.MethodsThis multicenter study included all patients with Kabuki syndrome who met the international consensus diagnostic criteria for KS. A total of 51 patients with genetically or clinically confirmed KS were enrolled. Among them, 11 had autoimmune cytopenias (autoimmune thrombocytopenia, autoimmune hemolytic anemia, or both) and 40 did not. Clinical manifestations, immune parameters, and comorbidities were compared between groups. Continuous variables were compared using the t test, while categorical variables were analyzed using the chi-square test.ResultsPatients with cytopenias were significantly older at diagnosis compared to those without cytopenias (10.5 ± 7.5 vs. 3.4 ± 4.9 years, p = 0.005). Gender distribution did not differ significantly between groups (p = 0.477). Hearing impairment was significantly more prevalent in patients without cytopenias (65.8%) than in those with cytopenias (18.2%) (p = 0.005). Conversely, hypogammaglobulinemia was markedly more common among patients with cytopenias (70%) compared to those without (22.9%) (p = 0.005). No statistically significant differences were observed in the prevalence of congenital cardiac abnormalities or endocrinopathies between the two groups. Regarding lymphocyte subsets, B cell lymphopenia and natural killer (NK) cell lymphopenia were significantly more frequent in the cytopenias group (33.3% vs. 6.7% for both, p = 0.036). Although T cell lymphopenia was more common in patients with cytopenias (55.6% vs. 30%), this difference did not reach statistical significance (p = 0.161).ConclusionApproximately 20% of KS patients exhibit autoimmune cytopenias. Autoimmune cytopenias in KS are associated with a higher frequency of hypogammaglobulinemia and B cell lymphopenia, indicating a more pronounced underlying immune dysfunction. These findings highlight the importance of proactive immunological evaluation and monitoring in KS patients presenting with cytopenias.Tabular data are included as downloadable supplement files.

IntroductionComplement C2 deficiency is a classical pathway defect associated with recurrent infections and autoimmunity. This case demonstrates the need for increased awareness amongst rheumatologists for the indications to suspect complement deficiency and also presents a unique presentation of C2 deficiency with hyper IgE.CaseA 34-year-old woman with systemic lupus erythematosus and rheumatoid arthritis diagnosed in adolescence presented with lifelong recurrent infections. Her history included meningitis in infancy, recurrent otitis media and sinusitis during childhood, and multiple pneumonias requiring hospitalization in adulthood with the development of bronchiectasis. Complement testing demonstrated a CH50 less than 13 U/mL with normal AH50, low C4, and normal C3. Complement studies were repeated by a rheumatologist and noted that CH50 was persistently low despite optimal autoimmunity control with anifrolumab and hydroxychloroquine, so she was referred to immunology.Immunologic testing showed IgE above 10,000 kU/L, IgM below 5 mg/dL, IgA 33 mg/dL, normal IgG with preserved subclasses except for low IgG4, and normal absolute eosinophil count. Absolute CD19 B cells were reduced at 58 cells/μL. Pneumococcal antibody titers were protective to only 8 of 23 serotypes above 1.3 mcg/L, while tetanus and diphtheria responses were intact. Serum protein electrophoresis was normal. Patient is not very atopic, with only slightly positive aeroallergen sensitization.Commercial genetic testing using a 574-gene inborn errors of immunity panel identified homozygous known pathogenic variants in C2 (c.841_849+19del in the splice site). Management includes optimizing vaccines, antibiotic prophylaxis, and consideration of immunoglobulin replacement.DiscussionThis case demonstrates a unique finding of hyper-IgE in C2 deficiency. We do not know if the two findings are related, and we also cannot rule out that her hyper IgE is an immunologic consequence of anifrolumab targeting interferon, causing a downstream Th2 phenotype. This case also demonstrates that rheumatologists should always refer autoimmune patients with infectious histories and that persistently low CH50 is concerning for complement deficiency. Earlier identification of complement deficiencies may prevent diagnostic delays and improve clinical outcomes.Tabular data are included as downloadable supplement files.

Individuals with Down syndrome (DS) are known to have increased susceptibility to infections, yet the extent of underlying immune dysfunction remains under-characterized. This retrospective study evaluates immune abnormalities in individuals with DS referred for immunologic assessment. A review of electronic records (2010–2023) identified 17 unique patients (mean age 7.4 years). Recurrent infections included otitis media (29 %), viral URIs (24 %), and bacterial LRIs (24 %), though infection types were often poorly documented. Lab abnormalities were frequent: 15/17 (88 %) had ≥1; 9/17 (53 %) had absolute lymphopenia, and among those tested, 6/10 (60 %) had T-, B-, and/or NK-cell lymphopenia. Low immunoglobulins were seen in 7/14 (50 %). Pneumococcal titers were non‑protective in 9/12 (75 %) after the primary series, with only 50 % protective post‑booster. Interventions included additional pneumococcal vaccines (8/12, 67 %) and immunoglobulin therapy (1/17, 6 %). Findings underscore the high rate of immune abnormalities in individuals with DS and support routine immunologic evaluation and tailored interventions. Though referral bias may overestimate prevalence, results highlight the need for proactive immune monitoring in this population.

Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of genetic disorders affecting the development and function of the immune system. While IEIs traditionally present with recurrent infections, an increasing number of cases manifest with early-onset severe atopy, including atopic dermatitis, food allergies, asthma, and allergic rhinitis—features that are often overlooked. This can lead to delayed diagnosis and treatment, which is crucial for IEI patients due to the risk of severe infections. We conducted a literature search and reviewed all IEIs that can present with early-onset severe atopy. The hallmark features of these disorders often include early-onset, persistent, and severe atopic dermatitis, food allergies, and recurrent episodes of asthma, which may be refractory to treatments. Additionally, we discuss the importance of recognizing such severe atopy as a potential indicator of an underlying immune deficiency, particularly when accompanied by unusual infections, growth failure, or autoimmunity. This review aims to raise awareness of this association and emphasize the need for early diagnosis and genetic testing in patients with atypical or treatment-resistant allergic diseases, allowing for more timely diagnosis of underlying immunodeficiencies and appropriate treatments.

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder with an estimated prevalence of 1 in 10,000 live births worldwide. It presents with a spectrum of severity, ranging from mild to severe marked by characteristic facial features, growth delay, intellectual disability, heart defects, gastrointestinal issues, hearing loss, myopia, and frequent upper and lower respiratory infections. The majority of genetic variants found in CdLS are associated with variants in the NIPBL gene, which encodes a regulatory protein crucial for the function of the cohesin complex. We present an 8-year-old male with a history of dysmorphic facial features, global developmental delay, aortic coarctation, lagophthalmos, hearing loss, and recurrent upper and lower sinopulmonary infections. There is no family history of immunodeficiencies or other genetic syndromes and patients born outside the United States. Commercial whole-exome sequencing performed at 7 years of age revealed a heterozygous de novo pathogenic variant in NIPBL (c.8257 C>G, p.R2753G). Complete blood count with differential, basic lymphocyte subsets, and immunoglobulins were within normal limits. Patient was immune to varicella, hepatitis B, tetanus, and diphtheria post-vaccination but only had 1/23 strep pneumoniae titers above 1.3 ug/mL and only 4/23 above 0.5 ug/mL after primary Prevnar 13 series. Advanced phenotyping showed increased percentage of transitional B cells, increased proportion of CD8+ TEMRA cells, reverse CD4/CD8 ratio at 0.69, and normal mitogen-induced lymphocyte proliferation to PHA and ConA with PWM at 50% below the lower limit of normal. Patient given booster vaccination with Pneumovax and had improvement in strep pneumoniae titers to 16/23 protective above 1.3 ug/mL and decreased clinical infections. The cohesin protein complex plays a significant role in the immune system, and altered expression of immune-related genes in patients with CdLS may explain the varying degrees of immunodeficiency observed in these individuals. Although no specific immune defect has been universally identified in CdLS, and there are no established guidelines for managing immune issues or vaccination in this population, it is important to conduct clinical immunologic evaluations for CdLS patients who experience recurrent infections as booster vaccinations can significantly improve these patients’ quality of life.

BackgroundPediatric patients listed for solid organ transplantation are at high risk for undiagnosed inborn errors of immunity and secondary immunodeficiency. This study aimed to report the immunological characteristics of pediatric patients listed for solid organ transplant.MethodsA retrospective chart review was conducted on a cohort of 64 pediatric patients who underwent immunological evaluation prior to solid organ transplantation at a single institution. Data were collected from electronic medical records.ResultsThe majority of the patients were evaluated for multivisceral transplant (68%) and 52% of the 64 patients underwent transplantation. The mortality rate was 16%, with sepsis being the most common cause of death. Laboratory abnormalities included T (53%), B (12%), and NK (35%) cell lymphopenia, low immunoglobulin levels (22% IgG, 11% IgM, 11% IgA), and poor pneumococcal titers (67%). Genetic testing identified known monogenetic inborn errors of immunity in 2 patients.ConclusionThis study emphasizes the importance of immunological evaluation in pediatric patients listed for solid organ transplant. The findings support the need for tailored post-transplant care, including vaccination, monitoring of immunoglobulin levels, and genetic testing, as pre-transplant evaluation led to changes in patient management. Pre-transplant screening can identify underlying immunodeficiencies, guide immunosuppression protocols, and improve long-term transplant outcomes. Further research is needed to establish the broader applicability of genetic testing and optimize strategies for post-transplant complications. Immunological evaluation should be considered a valuable tool in optimizing pediatric solid organ transplant outcomes.

Kabuki syndrome is a rare disorder primarily associated with mutations in the KMT2D (autosomal dominant) and KDM6A (X-linked) genes. While these mutations may be linked to immune dysregulation, including humoral immunodeficiencies resembling common variable immunodeficiency with recurrent infections and impaired B cell memory differentiation [1], these associations are not well established. This study aims to further characterize immune dysregulation, clinical manifestations, and genetic variability in Kabuki syndrome to address this gap. This case series involves patients diagnosed with Kabuki syndrome at the University of Miami, following Institutional Review Board approval (Study #20240903). Electronic medical records were reviewed to analyze demographics, history of infections, autoimmunity, and relevant laboratory data. The study included seven patients (4 males and 3 females), aged 14 months to 26 years (mean: 11.7 years, median: 5 years). Hypogammaglobulinemia was observed in 6/7 patients (86%), with low IgG in 4/7 (57%), low IgA in 2/7 (29%), and low IgM in 3/7 (43%). Lymphopenia was identified in 3/7 patients (43%) for CD3, 3/7 (43%) for CD4, and in 2/7 (29%) for CD8. 1/7 patients (14%) showed significant B cell subset abnormalities. Pathogenic or likely pathogenic KMT2D mutations were detected in 6/7 patients (86%), while 2/7 (29%) had variants of uncertain significance (CEP250, SALL1, and SRCAP). A duplication at 2q22.1 was noted in 1/7 patients (14%) without a clear clinical phenotype. Recurrent infections occurred in 3/7 patients (43%), mainly involving upper respiratory infections, otitis media, and pneumonia. Autoimmunity was reported in 1/7 patients (14%) and lymphoproliferative disorders in 2/7 (29%). Intravenous immunoglobulin therapy was administered to 3/7 patients (43%) and 1/7 (14%) received prophylactic vaccines for low pneumococcal antibody titers. This study finds that patients with Kabuki syndrome exhibit significant immune dysregulation, including hypogammaglobulinemia, lymphopenia, and recurrent infections, which are linked to genetic variability such as pathogenic KMT2D mutations and variants of uncertain significance. These findings support the need for routine immune evaluations, genetic testing, and targeted therapies, including immunoglobulin replacement and additional vaccinations, to guide personalized management and improve patient outcomes.

Peanut allergy presents a significant and growing public health concern, marked by its increasing prevalence and potential for severe allergic reactions. Traditional diagnostic methods, such as skin prick testing and serum IgE assays, serve as cornerstone approaches but often fall short in specificity, sensitivity, and risk stratification. This has driven the development of innovative diagnostic technologies, including component-resolved diagnostics, basophil activation tests, bead-based epitope assays, molecular diagnostics, and artificial intelligence applications. These advancements promise greater diagnostic precision, improved patient stratification, and tailored management strategies. However, challenges such as high costs, accessibility issues, and the need for standardized protocols hinder their widespread clinical adoption. This review explores the evolution of peanut allergy diagnostics, comparing traditional and emerging methodologies, and discusses their clinical implications, limitations, and future directions. The integration of advanced technologies with established approaches holds the potential to revolutionize peanut allergy diagnosis and management, ultimately enhancing patient care and outcomes.

The patient is a 3-year-old female with a history of hypoxic-ischemic encephalopathy, cerebral palsy, global developmental delay, hypotonia, epilepsy, feeding intolerance with known aspirations, and chronic lung disease who presented to immunology for evaluation of recurrent, severe upper and lower respiratory tract infections. In the past year, she reported monthly upper respiratory infections, three of which progressed to pneumonia requiring antibiotic treatment, and two of which required hospitalization for severe respiratory failure. She denied lifetime otitis, sinusitis, cutaneous, or other invasive or serious infections. Immunological evaluation demonstrated normal lymphocyte subsets, B cell phenotyping, naïve/memory T cell phenotyping, immunoglobulins, non-protective tetanus titer, protective diphtheria titer, and protective hepatitis B titer. The patient had 2/23 Streptococcus pneumoniae titers protective above 1.3 mcg/mL after initial Prevnar 13 administration and then only 4/14 S. pneumoniae titers protective above 1.3 mcg/mL after Pneumovax 23 booster. The patient had normal lymphocyte proliferative responses to PHA, PWM, soluble anti-CD3, and anti–CD3+IL-2 though decreased to soluble anti–CD+anti-CD28. Genetic testing detected a heterozygous known pathogenic VARS2 variant (c.1546G>T and p.Glu516*) associated with autosomal recessive combined oxidative phosphorylation deficiency in addition to 9p24.2 duplication. VARS2 encodes a key enzyme for mitochondrial protein synthesis 1. 9p duplication is associated with global developmental delay similar to the patient’s phenotype but has not been specifically linked to abnormalities in the immune system. Despite initial treatment with prophylactic azithromycin and revaccination for S. pneumoniae, the patient developed COVID-19 pneumonia and rhino enterovirus with severe respiratory failure requiring two separate hospitalizations over three months and no significant improvement in strep pneumoniae titers. Subcutaneous immunoglobulin replacement therapy was initiated, and she has been on biweekly subcutaneous immunoglobulin replacement for four months with symptomatic improvement and no further infectious diagnosis. This case highlights that patients with 9p duplication and other rare genetic disorders are at risk for immune dysfunction and can benefit from replacement immunoglobulin. Patients with rare genetic disorders that have not been previously linked to immune dysfunction should be evaluated by an immunologist if recurrent infections.

Respiratory symptoms are among the most common presentations of inborn errors of immunity (IEI) and acquired immunodeficiencies in children. Pediatric pulmonologists are often the first to evaluate these patients, yet immunologic evaluations remain underutilized due to diagnostic complexity and limited familiarity with immune testing. Not all patients will have access to a timely consultation with an immunologist. This review provides a practical framework to aid pediatric pulmonologists in identifying, evaluating, and managing immune dysfunction in children with respiratory disease. It outlines clinical indicators, such as recurrent infections, bronchiectasis, failure to thrive, and syndromic features, and describes the utility and limitations of key immunologic tests. Stepwise diagnostic strategies are presented, from initial laboratory screening to functional assays and genetic testing. Common IEI with respiratory manifestations, including antibody deficiencies, combined immunodeficiencies, phagocytic disorders, and immune dysregulation syndromes, are reviewed. The article also addresses acquired immunodeficiencies, diagnostic mimics, and principles of pulmonary co-management, including prophylaxis and long-term follow-up. Early recognition and collaborative care can improve outcomes and prevent irreversible pulmonary damage in this vulnerable population.

Background: Approximately 5%-8% of U.S. children have experienced an anaphylactic reaction. Studies assessing parent knowledge regarding the usage of epinephrine autoinjectors found that over two-thirds of parents could not correctly use autoinjectors. Family caregivers need education about triggers, prevention, symptom recognition, and plans of action for anaphylactic reactions. Objective: The overarching goal of this quality improvement project is to improve family caregiver management of food allergies in pediatric patients. Methods: The evidence-based, practice improvement project involved the development of a 5 ½-minute video with an allergy action plan that could be accessed via quick response code as an educational material provided to caregivers. A pre-post survey design was used to evaluate caregiver knowledge and satisfaction with the video-based educational program. Results: Outcomes showed that caregiver knowledge significantly increased (p = .007). All caregivers (N = 10; 100%) indicated high satisfaction with the education. Conclusions: The use of video-based education with an allergy action plan is a practical and sustainable way to bridge the gap of inadequate caregiver education. Leveraging the use of caregivers' smartphones to access video-based educational resources is a model that could be applied to various diseases and treatment regimens. Implications for Nursing: Nurses often struggle with time constraints to provide thorough patient education. This method may be a more efficient and effective way for nursing to provide supplemental patient education.

Peanut allergy, a significant public health issue, poses challenges due to its potential for life-threatening anaphylaxis and profound impact on quality of life. Traditional management approaches, including allergen avoidance and epinephrine administration, are effective in mitigating acute symptoms but do not address the underlying allergy or long-term disease burden. Recent advances in immunotherapy and biologics, as well as innovative technologies such as gene editing and microbiome modulation, have introduced promising pathways for desensitization and sustained unresponsiveness. This review provides a comprehensive exploration of emerging therapies for peanut allergy, including oral, sublingual, and epicutaneous immunotherapy, biologic agents, gene-editing techniques, and novel drug therapies. We discuss their mechanisms, clinical efficacy, and associated challenges, emphasizing the potential for these innovations to revolutionize peanut allergy treatment. Despite significant progress, barriers such as adverse reactions, cost, and limited access remain. Addressing these challenges through further research and standardization could transform the future of peanut allergy management.

Non-IgE immune-mediated gastrointestinal disorders constitute a heterogeneous group of enigmatic conditions that are on the rise. This category encompasses entities like food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). These are immune-mediated reactions to certain foods without the involvement of allergen-specific IgE in their pathogenesis. Eosinophilic esophagitis (EoE) is also included in this group, acknowledged for its mixed IgE and non-IgE-mediated characteristics. The diagnostic landscape is fraught with challenges, given the poorly understood nature of these disorders and their propensity to manifest with varying and overlapping clinical presentations, typically emerging in infancy with common potential triggers such as cow’s milk and soy. Presently, confirmatory testing for most of these conditions is limited and invasive, emphasizing the pivotal role of a thorough history and physical examination in reaching a diagnosis. Notably, there are limited guidelines for diagnosis and management for most of these disorders. This article elucidates the key distinctions among these disorders, provides an overview of existing diagnostic and therapeutic approaches, and addresses existing knowledge and research gaps. The considerable impact on the quality of life of non-IgE immune-mediated allergic disorders of the gastrointestinal tract, which can result in debilitating complications such as nutritional deficiencies, mental health disorders, and eating disorders, underscores the urgency for comprehensive exploration and management strategies.